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Cutting Edge: Genetic Variation Influences FcRI-Induced Mast Cell Activation and Allergic Responses¹

Yumi Yamashita^*, Nicolas Charles^*, Yasuko Furumoto^*, Sandra Odom^*, Toshiyuki Yamashita^*, Alasdair M. Gilfillan, Stephanie Constant, Molly A. Bower, John J. Ryan and Juan Rivera^2,*

^* Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases and Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC 20037; and Department of Biology, Virginia Commonwealth University, Richmond, VA 23284

Mast cell responses are influenced by a diverse array of environmental factors, but little is known about the effect of genetic background. In this study, we report that 129/Sv mice had high levels of circulating IgE, increased expression of the high-affinity receptor for IgE (FcRI), and greater sensitivity to anaphylaxis when compared with C57BL/6 mice. Bone marrow-derived mast cells (BMMCs) from 129/Sv mice showed more robust degranulation upon the engagement of FcRI. Deficiency of the Src family kinase Lyn enhanced degranulation in 129/Sv BMMCs but inhibited this response in C57BL/6 cells. C57BL/6 lyn^–/– BMMCs had reduced expression of the Src family kinase Fyn, and increasing its expression markedly enhanced degranulation. In human mast cells the silencing of Lyn or Fyn expression resulted in hyperdegranulation or hypodegranulation, respectively. The findings demonstrate a genetic influence on the extent of a mast cell’s response and identify Fyn kinase as a contributory determinant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Programs of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) and NIH Grants AI 059638 (to J.J.R.) and AI067254 (to S.C.). N.C. was supported by the Fondation pour la Recherche Médicale of France.

² Address correspondence and reprint requests to Dr. Juan Rivera, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health, Building 10, Room 9N228, Bethesda, MD 20892-1820. E-mail address: juan_rivera{at}nih.gov

³ Abbreviations used in this paper: MC, mast cell; BMMC, bone marrow-derived MC; HuMC, human MC; PLC, phospholipase; shRNA, short hairpin RNA; WT, wild type.